Transdermally administered acetylcysteine as mucolytic agent

ABSTRACT

Device for transdermal administration of N-Acetyl-L-cysteine, optionally encompassing salts, prodrugs and metabolites thereof, optionally together with pharmaceutically acceptable carrier(s) to a human being or an animal in order to achieve a mucolytic effect. Use of a mucolytic compound comprising N-Acetyl-L-cysteine, optionally encompassing salts, prodrugs and metabolites thereof, optionally together with pharmaceutically acceptable carrier(s), for the manufacture of a composition for achieving a mucolytic effect in a human being or an animal. Method for achieving a mucolytic effect in a living body by transdermal administration of a compound comprising N-Acetyl-L-cysteine, optionally encompassing salts, prodrugs and metabolites thereof, optionally together with pharmaceutically acceptable carrier(s).

This application is the national phase under 35 U.S.C. §371 of prior PCTInternational Application No. PCT/SE97/00483 which has an Internationalfiling date of Mar. 21, 1997 which designated the United States ofAmerica, the entire contents of which are hereby incorporated byreference.

This invention relates to use of N-Acetyl-L-cysteine, optionallyencompassing salts, prodrugs and metabolites thereof, for themanufacturing of a medicament to be administered transdermally forachieving a mucolytic effect and to methods of treating diseases beingtreatable with a mucolytic agent by transdermal administration ofN-Acetyl-L-cysteine, optionally encompassing salts, prodrugs andmetabolites thereof.

BACKGROUND

N-Acetyl-L-cysteine, C₅H₉NO₃S, is an expectorant. Its synthesis wasdisclosed in Smith et al., J. Org. Chem., 1961;26:820.N-Acetyl-L-cysteine decreases the viscosity of mucous and purulentexpectorate. The mucolytic effect after peroral administration inconnection with bronchitis is though not well-documented. However,several investigations have proved effect just below the significancelimit. Anyhow, the patients' wellbeing during treatment withN-Acetyl-L-cysteine is significant. N-Acetyl-L-cysteine is registered asa mucolytic agent for peroral administration under trade marks such asFabrol®, Inspir® and Mucomust®.

N-Acetyl-cysteine has a low bioavailability, only about 4-10%, whenadministered perorally, see Mack R. Holdiness, “ClinicalPharmacokinetics of N-Acetylcysteine”, Clin. Pharmacokinet.,1991;20(2):123-134. The following references confirm the lowbioavailability of N-Acetyl-L-cysteine: L. Borgström et al.,“Pharmacokinetics of N-Acetylcysteine in Man”, Eur J Clin Pharmacol.1986;31:217-222, L. Borgström et al., “Dose dependent pharmacokineticsof N-Acetylcysteine after oral dosing to man”, Biopharmaceutics & DrugDisposition, 1990(II):131-136, B. Olsson et al., “Pharmacokinetics andBioavailability of Reduced and Oxidized N-Acetylcysteine”, Eur J ClinPharamcol. 1988;34:77-82. Martindale, “The Extra Pharmacopoeia”, London,1993, recommends a peroral dosing of 200 mg three times daily to adults,200 mg once daily for children up to 2 years and 200 mg twice daily forchildren aged 2 to 6 years.

Deutsche Apotheker Zeitung; 34; 1990 indicates that the maximum plasmalevel is reached 2 to 3 hours after oral administration. The samereference indicates 4% bioavailability upon oral administration.

Currently the mucolytic effect is achieved by inhalation or peroraladministration of N-Acetyl-L-cysteine. The inhalation route can only beused for temporary relief and several dosings per day are necessary.Administration of N-Acetyl-L-cysteine through the oral route is hamperedby a low bioavailability of the drug due to an extensive first-passmetabolism and side effects such as nausea and skin disorders, likerash.

The above disadvantages are removed or reduced upon administeringN-Acetyl-L-cysteine transdermally.

N-Acetyl-L-cysteine is a fairly unstable drug in aqueous formulation.This could be improved by incorporation into a lipophilic medium likethe one used in pressure sensitive adhesives, such as polyisobutylenes,acrylates and silicone derivatives.

PRIOR ART

Transdermal administration of N-Acetyl-L-cysteine is known from a fewpatents, e.g. from WO 95/00136 (ARNDT ET AL.) for treatinghyperkeratosis, and WO 93/07903 (DECKNER ET AL.) wherein is disclosedcertain cationic polymers which may improve transdermal penetration of anumber of drugs, such as N-Acetyl-L-cysteine. Anyhow there is no patentwhich discloses transdermal administration of N-Acetyl-L-cysteine forachieving a mucolytic effect.

EP 0481294 (SPIRIG AG) discloses oral administration of acetylcysteine,but does not mention transdermal administration thereof.

Only sparse studies on skin permeation of N-Acetyl-L-cysteine have beenreported in the literature with the aim to use N-Acetyl-L-cysteine as amodel substance in connection with experiments to compare skinpermeability between different animal species such as rat, rabbit, pig,monkey and man, see Methodius J. Bartek et al., “Skin permeability invivo in rat, rabbit, pig and man”, 32nd Annual Meeting of the Societyfor Investigative Dermatology Inc., Boston, Mass., 1971, June 18-20, andRonald C. Wester et al., Clin. Pharmacokinet., 1992;23(4):253-266. Frominter alia the above Bartek reference it is evident that the transdermalpene-tration of N-Acetyl-L-cysteine hitherto was considered to be verylow.

There is no literature reference which discloses transdermaladministration of N-Acetyl-L-cysteine for achieving a mucolytic effect.

Hence the present invention being transdermally administeredN-Acetyl-L-cysteine as mucolytic agent, as further described below, isboth new and inventive over prior art.

OBJECTS OF THE INVENTION

The above mentioned disadvantages and side effects are removed orreduced when N-Acetyl-L-cysteine is administered transdermally.

Accordingly, a first object of the present invention is to provide adevice for transdermal administration of N-Acetyl-L-cysteine, optionallyencompassing salts, prodrugs and metabolites thereof, for achieving amucolytic effect. The administration can be to a human being or to ananimal. The mucolytic effect is for treating any kind of mucous andpurulent expectorates, such as, but not exclusively, mucous and purulentexpectorates occuring in association with upper and lower respiratoryinfections, including chronic bronchitis and asthma, and with cysticfibrosis, emphysema, tracheostomy and post-operative pulmonarycomplications. The pharmacological effect is primarily achieved byreduction of the viscosity for the mucous and purulent expectorates.

A second object of the invention is to provide use of a mucolyticcompound comprising N-Acetyl-L-cysteine for the manufacture of acomposition to be administered transdermally for treating mucous andpurulent expectorates, primarily by decreasing their viscosity, orconditions associated with mucous and purulent expectorates.

A third object of the invention is to provide a method of treatingdiseases, in humans or animals, which are treatable with mucolyticagents by administering N-Acetyl-L-cysteine transdermally.

Other objects of the invention will become apparent to one skilled inthe art, and still other objects will become apparent hereinafter.

SUMMARY OF THE INVENTION

The present invention relates to transdermal administration ofN-Acetyl-L-cysteine, optionally encompassing salts, prodrugs andmetabolites thereof for achieving a mucolytic effect. This effect isprimarily achieved through the systemic effect of N-Acetyl-L-cysteinewhereby in the first place the viscosity of mucous and purulentexpectorates is decreased. Anyhow, other mechanisms of actions are notexcluded.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D are schematic drawings of different types of devices fortransdermal delivery of drugs.

FIG. 2 is a diagram showing in vitro skin permeation ofN-Acetyl-L-cysteine from different solvents according to Example 2.

FIG. 3 is a diagram showing in vitro permeation of N-Acetyl-L-cysteinethrough different membranes in accordance with Example 3.

FIG. 4 is a diagram showing in vitro release of N-Acetyl-L-cysteine fromdifferent transdermal systems in accordance with Examples 4 and 5.

DETAILED DESCRIPTION OF THE INVENTION

Transdermal delivery of drugs can be accomplished from topical productssuch as ointments or cremes or from transdermal devices. The presentinvention relates to administration via transdermal devices, whichusually are called transdermal patches.

Devices usable as transdermal patches can be categorized in manydifferent ways. A comprehensive categorization of transdermal devices isfound in Steven Wick, “Developing A Drug-In-Adhesive Design ForTransdermal Drug Delivery”, Adhesives Age, 1995; 38(10):18-24, whichhereby is incorporated by reference. Wick essentially dividestransdermal devices into the below four main groups:

the reservoir type, in which the drug is placed in a liquid or a gel andis delivered to the skin across a rate-moderating membrane;

the matrix type, in which the drug is placed within a non-adhesivepolymeric material, typically a hydrogel or soft polymer;

the drug-in-adhesive type, in which the drug is placed within anadhesive polymer;

the multi-laminate type, which is similar to the drug-in-adhesivedesign, but which incorporates an additional layer of pressure sensitiveadhesive to cover the entire device and affix it to the skin.

The above four main types of transdermal devices are schematicallyillustrated in FIGS. 1A-1D.

A fifth important type, not mentioned by Wick, is the iontophoretictype, in which an electrical potential gradient is used for transferringthe drug through the skin—see further e.g. Parminder Singh et al,“Iontophoresis in Drug Delivery: Basic Principles and Applications”,Critical Reviews in Therapeutic Drug Carrier Systems, 1994; 11(2&3):161-213.

The above split-up into groups is not very strict as variations andcombinations of each may be envisaged. So may a multi-laminate typedevice encompass a device with many layers in a sandwich construction,such as the drug in one layer, excipients such as enhancers in a furtherlayer, a membrane in another layer and an adhesive in still anotherlayer. Or it could be composed of several drug-in-adhesive layers orcombinations of the above layers.

The liquid or gel used in the above reservoir type device could behydrophilic or lipophilic, such as water, alcohols, mineral oils,silicone fluids, various copolymers, such as ethylene vinyl acetate,vinyl acetate or polyvinyl alcohol/polyvinyl pyrrolidine. The reservoirmay also include dyes, inert fillers, diluents, antioxidants,penetration enhancers, stabilizers, solubilizing agents and otherpharmacologically inactive pharmaceutical agents being well known in theart.

The adhesives used are generally of three types, being the rubber type,encompassing inter alia polyisobutylenes, the acrylate type and thesilicone type. The adhesives may be chemically modified and may have awide range of molecular weights. To the adhesive could be added severaltypes of excipients such as fillers, stabilizers, plasticizers,buffering agents, penetration enhancers, penetration retarders,solubilizing agents and other pharmaceutical ingredients being wellknown in the art.

Polymer films which may be used for making the rate-moderating membraneinclude, without limitation, those comprising low density polyethylene,high density polyethylene, ethyl vinyl acetate copolymers and othersuitable polymers.

The backing layer serves the purposes of preventing passage of the drugor environmental moisture through the surface of the patch distant fromthe skin, and also for providing support for the system, where needed.The backing layer may be choosen so that the end product is appealing tothe users, whether children, adults, elderly people or other customergroups. The backing layer is impermeable to the passage ofN-Acetyl-L-cysteine or inactive ingredients being present in theformulation and can be flexible or nonflexible. Suitable materialsinclude, without limitation, polyester, polyethylene terephthalate, sometypes of nylon, polypropylene, metallized polyester films,polyvinylidene chloride and aluminium foil.

The release liner can be made of the same materials as the backinglayer.

As will be clear further below the invention according to the presentapplication encompasses administration of N-Acetyl-L-cysteine via allhitherto known types of devices for transdermal administration. Mainlythe above categorization will be adhered to in this application. Anyhow,this does not exclude that transdermal devices which might fit betteraccording to some other categorization also are included in the presentinvention.

It is well known in the art that the properties of the skin as suchinfluence the penetration of the drug through the skin into the systemiccirculation. It could thus be said that the skin controls the drugpenetration rate. Anyhow, as the skin as such is no part of the presentinvention the behaviour of the skin in connection with transdermaladministration will not be discussed in detail. It is also well acceptedin the art that when rate controlling properties are attributed to atransdermal device is meant properties associated with the release ratefrom the device as such. It is also evident that when a transdermaldevice is designed to exhibit a certain release performance theproperties of the skin need be taken into consideration during thedesign process.

The rate control ability is often a very important feature for atransdermal device in order to deliver the correct drug amount to thepatient at the correct time. Thereby maximum efficacy is achieved whileside effects are minimized. Many factors influence the rate controlability of a transdermal device. In the below Table 1 the most importantsuch factors are listed and their influence in the respective devicetype is marked. A plus sign indicates that the influence is strong. Theabsence of a plus sign does not exclude that the corresponding factorhas at least some influence.

TABLE 1 TYPE OF DEVICE Multi- Factor Reservoir Matrix Drug-in-adhesivelaminate -Polymer type(s) + + + + -Modification of + + + the polymer(s)-Activity, i.e. + + + + concentration, of drug, e.g. supersaturation-Additives in polymer(s) Enhancer(s) + + + + Cyclo- + + + + dextrine(s)Retarder(s) + + + + -pH-adjustment + + + + -Solubilizer(s) + + + +-Emulsifier(s) + + + + -Membrane(s) + Hydrophilic + Lipophilic +Thickness + Pore Size + Density + -Chemical sta- + + + + bilizer(s)

As a comparably high loading of N-Acetyl-L-cysteine is needed forachieving the desirable therapeutic effect the reservoir type device andthe multilaminate type device, including several drug-containing layers,are presently considered to be the best modes for making the presenttransdermal delivery of N-Acetyl-L-cysteine.

It is also desirable to include, at least in some device types, one ormore transdermal penetration enhancing substance(s) in order to increasethe amount of N-Acetyl-L-cysteine that may penetrate the skin and thateventually may reach the systemic cirkulation. Enhancers suitable in thepresent invention may be categorized in the below groups, althoughenhancers not belonging to any of these groups are not excluded.

alcohols, such as short chain alcohols, e.g ethanol and the like, longchain fatty alcohols, e.g. lauryl alcohols, and the like, andpolyalcohols, e.g. propylene glycol, glycerin and the like;

amides, such as amides with long aliphatic chains, or aromatic amideslike N,N-diethyl-m-toluamide;

amino acids;

azone and azone-like compounds;

essential oils, i.e. essential oils or constituents thereof, such as1-carvone, 1-menthone and the like;

fatty acids and fatty acid esters, such as oleic acid, lauric acid andthe like, further esters of fatty acids, such as isopropyl myristate,and various esters of lauric acid and of oleic acid and the like;

macrocyclic compounds, such as cyclopentadecanone and cyclodextrins;

phospholipid and phosphate compounds, such as phospholipids;

2-pyrrolidone compounds; and

miscellaneous compounds, like sulphoxides, such as dimethyl sulphoxides,and fatty acid ethers, such as Laureth-9 and polyoxylaurylether.

Combinations of enhancers from different groups in the abovecathegorization may prove to be very useful and efficient.

For overviews of enhancers, see further e.g. G.C. Santus et al.,“Transdermal enhancer patent literature”, Journal of Controlled Release,1993;25:1-20 and Eric W. Smith et al., “percutaneous penetrationenhancers”,CRC Press Inc., 1995.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are intended to illustrate but not to limit thescope of the invention, although the embodiments named are of particularinterest for our intended purposes.

MATERIALS AND APPARATUS USED IN THE EXAMPLES Materials

N-Acetyl-L-cysteine, Fluka

Sodium hydroxide, Merck

Propylene glycol, Merck

Azone, Discovery Therapeutics Inc.

Ethanol 99.9%, De Danske Spritfabrikker

Hydrochloric acid, Merck

Polycarbonate membrane 0.2 μm in pore diameter, Whatman

Polycarbonate membrane 0.6 μm in pore diameter, Whatman

Polyester membrane 0.2 μm in pore diameter, Whatman

Polyester membrane 0.6 μm in pore diameter, Whatman Cotran 9711, 3M

Polyester film S 2016, Rexam Release

Polyester film Scotchpak 1220, 3M

Polyester film Scotchpak 1109, 3M

Eudragit RL 30 D, Röhm GmbH Chemische Fabrik

Eudragit NE 30 D, Röhm GmbH Chemische Fabrik

Plastoid E35H, Röhm GmbH Chemische Fabrik

Polyvidone 90, BASF

Span 20, Sorbitanmonolaurate, Maximex

MA-24 Medical Grade Adhesive, Adhesives Research Inc.

ETA-2 Medical Grade Adhesive, Adhesives Research Inc.

Durotak 387-2287, National Starch and Chemical B.V.

Triethyl citrate, Fluka

Sodium bisulfite, Sigma

Apparatus

Franz diffusion cells

Coating equipment: RP Print Coat Instrument LTD., Type KCC 202 ControlCoater System with vacuum bed and rods (100 and 400 μm)

UV-spectrophotometer

Drug Release Apparatus 5, paddle over disk,.described in USP 23, p. 1797

HPLC-device: LKB 2150 pump

LKB 2141 variable wavelength monitor

LKB 2221 integrator

Marathon-XT autosampler (20 μl injected) connected to a MultiTemperature 111 cooling bath adjusted to 4° C.

Analytical column, 25 cm×4.0 mm i.d., packed with Lichrosorb RP18, 5 μm.

The column was eluted isocratically at ambient temperature with a mobilephase consisting of water-acetonitrile (970:50 v/v) adjusted withdiluted phosphoric acid to a pH=3. The flow rate was 1.0 ml/min. and thecolumn effluent was monitored at 220 nm.

Example 1

Analysis of the receptor solutions described in Examples 2 and 3, and ofthe stability samples described in Example 6.

Quantitative determination of N-Acetyl-L-cysteine in the receptorsolution samples from the skin permeation studies in Example 2 and fromthe membrane permeation studies in Example 3, and quantitativedetermination of N-Acetyl-L-cysteine in the samples from the stabilitystudies in Example 6, was done by the HPLC method described underApparatus.

Example 2

In vitro skin permeation studies from solutions of N-Acetyl-L-cysteine.

Solution 1

500 mg N-Acetyl-L-cysteine was dissolved in 5 ml demineralized water.

The pH of the solution was adjusted to 5 by the addition of sodiumhydroxide.

Solution 2

250 mg N-Acetyl-L-cysteine was dissolved in 5 ml propylene glycol.

Solution 3

250 mg N-Acetyl-L-cysteine was dissolved in 5 ml propylene glycolcontaining 50 mg/ml of azone.

Solution 4

500 mg N-Acetyl-L-cysteine was dissolved in 5 ml ethanol.

In vitro permeation of N-Acetyl-L-cysteine from the solutions 1, 2, 3and 4 through dermatomed pig skin was investigated in Franz diffusionCells.

Skin pieces with a thickness of approximately 765 μm were dermatomedfrom full thickness pig skin and mounted in glass diffusion cells withan available diffusion area of 1.8 cm². Pig skin is a fully acceptedmodel for human skin. The solutions 1, 2, 3 and 4 were appliedseparately on the skin surfaces and the dermal sides were all exposed to12.1 ml receptor solution consisting of 0.0001M hydrochloric acidequilibrated to 37±1° C.

Permeation of N-Acetyl-L-cysteine was followed by removing samplesperiodically and measuring the concentration by the HPLC methodaccording to Example 1. The cumulative amount of N-Acetyl-L-cysteineappearing in the receptor solution versus time is shown in FIG. 2. Anincrease in the permeated amount of N-Acetyl-L-cysteine is seen in thefollowing order: Propylene glycol, water, ethanol and propylene glycolcontaining 5% azone added used as solvents. The estimated fluxes ofN-Acetyl-L-cysteine are in the range from approximately 4 to 48 μg/cm²/hfor the above solvents without enhancer added. The results show that itis possible to optimize the flux of N-Acetyl-L-cysteine through the skinby using an appropriate solvent. A surprisingly high rate of permeationwas observed for the solution with added azone as about 3000 μg/cm² waspermeated after 20 hours.

Example 3

In vitro permeation studies across artificial membranes from solutionsof N-Acetyl-L-cysteine, imitating the reservoir type transdermal device.

Solution 5

50 mg N-Acetyl-L-cysteine was dissolved in 5 ml demineralized water.

Solution 6

50 mg N-Acetyl-L-cysteine was dissolved in 5 ml ethanol.

In vitro permeation of N-Acetyl-L-cysteine from the solutions 5 and 6across 5 different types of artificial membranes was investigated inFranz diffusion cells.

Artificial membranes of the following types were studied: Whatman 0.2 μmPC (polycarbonate), Whatman 0.6 μm PC (polycarbonate), Whatman 0.2 μmPET (polyester), Whatman 0.6 μm PET (polyester) and Cotran 9711(microporous polyethylene film). The membranes were mounted in glassdiffusion cells with an available diffusion area of 1.8 cm². Solution 5was applied on the surfaces on all the above Whatman membranes whilesolution 6 only was applied on Cotran 9711. The opposite sides of themembranes were all exposed to 12.1 ml receptor solution consisting of0,0001M hydrochloric acid equilibrated to 37±1° C. Permeation ofN-Acetyl-L-cysteine was followed by removing samples periodically andmeasuring the concentration by the HPLC method according to Example 1.The cumulative amount of N-Acetyl-L-cysteine appearing in the receptorsolution versus time is shown in FIG. 3. An increase in the permeatedamount of N-Acetyl-L-cysteine is seen in the following order of usedmembranes: Whatman 0.2 μm PET, Whatman 0.2 μm PC, Whatman 0.6 μm PC,Whatman 0.6 μm PET and Cotran 9711.

The results show that it is possible to control the release rate ofN-Acetyl-L-cysteine from a reservoir type device by the choice ofsolvent and of membrane.

Example 4

Transdermal drug delivery systems with N-Acetyl-L-cysteine as the activesubstance.

System 1 (Drug-in-adhesive Type, Acrylate)

2.5 g N-Acetyl-L-cysteine and 350 mg Span 20 were dispersed in 10 gETA-2 Medical Grade Adhesive to give the drug gel. The drug gel wassolvent cast onto a polyester film, S 2016, by means of the coatingequipment (wet layer=400 μm). After drying at 80° C. for 10 minutes, apolyester film, Scotchpak 1220, was laminated onto the dried drug gel.The resulting sheet was die-cut into patches which were kept at roomtemperature until use. The concentration of N-Acetyl-L-cysteine in thepatches was approximately 4 mg/cm².

System 2 (Drug-in-adhesive Type, Acrylate)

2.5 g N-Acetyl-L-cysteine and 350 mg Span 20 were dispersed in 10 gDurotak 387-2287 to give the drug gel. The drug gel was solvent castonto a polyester film, S 2016, by means of the coating equipment (wetlayer=400 μm). After drying at 80° C. for 10 minutes, a polyester film,Scotchpak 1220, was laminated onto the dried drug gel. The resultingsheet was die-cut into patches which were kept at room temperature untiluse. The concentration of N-Acetyl-L-cysteine in the patches wasapproximately 4 mg/cm².

System 3 (Drug-in-adhesive Type, Polyisobutylene)

5 g N-Acetyl-L-cysteine and 700 mg Span 20 were dispersed in 20 g MA-24Medical Grade Adhesive to give the drug gel. The drug gel was solventcast onto a polyester film, S 2016, by means of the coating equipment(wet layer=400 μm). After drying at 80° C. for 10 minutes, a polyesterfilm, Scotchpak 1220, was laminated onto the dried drug gel. Theresulting sheet was die-cut into patches which were kept at roomtemperature until use. The concentration of N-Acetyl-L-cysteine in thepatches was approximately 3 mg/cm².

System 4 (Multi-laminate Type, Waterbased Acrylate)

4 g N-Acetyl-L-cysteine was dispersed in a mixture of 12.8 g Eudragit RL30 D, 12.8 g PVP gel (20% Polyvidone 90 swelled in water) and 4 gpropylene glycol to give the drug gel. The drug gel was solvent castonto a polyester film, S 2016, by means of the coating equipment (wetlayer=400 μm). After drying at 80° C. for 10 minutes, an adhesive layercon-sisting of Plastoid E35H (wet layer=100 μm) coated on a polyesterfilm, S 2016, was laminated onto the dried drug gel. The polyester film,S 2016, in contact with the drug gel was removed, and Scotchpak 1220 waslaminated onto the drug gel as backing. The resulting sheet was die-cutinto patches which were kept at room temperature until use. Theconcentration of N-Acetyl-L-cysteine in the patches was approximately1,5 mg/cm².

System 5 (Multi-laminate Type, Waterbased Acrylate)

4 g N-Acetyl-L-cysteine was dispersed in a mixture of 12.8 g Eudragit RL30 D, 12.8 g PVP gel (20% Polyvidone 90 swelled in water), 4 g propyleneglycol and 200 mg 1M sodium hydroxide solution to give the drug gel. Thedrug gel was solvent cast onto a polyester film, S 2016, by means of thecoating equipment (wet layer=400 μm). After drying at 25° C. for 2hours, an adhesive layer consisting of Plastoid E35H (wet layer=100 μm)coated on a polyester film, S 2016, was laminated onto the dried druggel. The polyester film, S 2016, in contact with the drug gel wasremoved, and Scotchpak 1109 was laminated onto the drug gel as backing.The result-ing sheet was die-cut into patches which were kept at roomtemperature until use. The concentration of N-Acetyl-L-cysteine in thepatches was approximately 1,5 mg/cm².

System 6 (Multi-laminate Type, Waterbased Acrylate)

2.4 g N-Acetyl-L-cysteine was dispersed in a mixture of 3 g Eudragit NE30 D and 45 g Plastoid E35H to give the drug gel. The drug gel wassolvent cast onto a polyester film, S 2016, by means of the coatingequipment (wet layer=400 μm). After drying at 80° C. for 10 minutes, anadhesive layer consisting of Plastoid E35H (wet layer=100 μm) coated ona polyester film, S 2016, was laminated onto the dried drug gel. Thepolyester film, S 2016, in contact with the drug gel was removed andScotchpak 1109 was laminated onto the drug gel as backing.The resultingsheet was die-cut into patches which were kept at room temperature untiluse. The concentration of N-Acetyl-L-cysteine in the patches wasapproximately 1 mg/cm².

System 7 (Drug-in-adhesive Type, Waterbased Acrylate)

2.4 g N-Acetyl-L-cysteine was dispersed in a mixture of 3 g Eudragit NE30 D and 45 g Plastoid E35H to give the drug gel. The drug gel wassolvent cast onto a polyester film, S 2016, by means of the coatingequipment (wet layer=400 μm). After drying at 80° C. for 10 minutes, apolyester film, Scotchpak 1109, was laminated onto the dried drug gel.The resulting sheet was die-cut into patches which were kept at roomtemperature until use. The concentration of N-Acetyl-L-cysteine in thepatches was approximately 1 mg/cm².

System 8 (Multi-laminate Type, Waterbased Acrylate)

4 g N-Acetyl-L-cysteine was dispersed in a mixture of 25 g Eudragit RL30 D, 1.9 g triethyl citrate, 200 mg 1M sodium hydroxide solution and 20mg sodium bisulfite to give the drug gel. The drug gel was solvent castonto a polyester film, S2016, by means of the coating equipment (wetlayer=400 mm). After drying at 25° C. for 2 hours an adhesive layerconsisting of Plastoid E35H (wet layer=100 mm) coated on a polyesterfilm, S2016, was laminated onto the dried drug gel. The polyester film,S2016, in contact with the drug gel was removed, and Scotchpak 1109 waslaminated onto the drug gel as backing. The resulting sheet was die-cutinto patches which were kept at room temperature until use. Theconcentration of N-Acetyl-L-cysteine in the patches was approximately 1mg/cm².

In vitro release studies according to Example 5 were carried out on thesystems 1, 2, 3, 4, 5, 6 and 7 described above. The results of thesestudies are shown graphically in FIG. 4.

The results show that different release profiles can be achieved fromdifferent types of devices.

Example 5

In vitro release studies of the transdermal drug delivery systems 1, 2,3, 4, 5, 6 and 7 according to Example 4.

The apparatus used was Apparatus 5, paddle over disk, described underApparatus above. Patches of 7.1 cm² were applied to the disk assembly,using a suitable adhesive, with the release surface facing up.Thedissolution medium used was 600 ml of 0.0001M hydrochloric acidequilibrated to 32±0.5° C. Samples were withdrawn at 1, 2, 4, 8 and 16hours, respectively. The amount of N-Acetyl-L-cysteine in the sampleswas determined either by UV-spectrophotometry at 215 nm (Systems 1, 2and 3) or by the HPLC method described under Apparatus (Systems 4, 5, 6and 7) and the concentration of the respective systems was expressed inmg N-Acetyl-L-cysteine per cm².

Example 6

Stability studies were carried out on drug delivery Systems 5 and 8according to the above Example 4. Patches from these Systems 5 and 8were stored at room temperature and quantitative determination ofN-Acetyl-L-cysteine was done by the HPLC method described underApparatus after 0, 4 and 12 weeks of storage respectively. The resultsof these studies are shown in Table 2 below.

TABLE 2 STABILITY OF N-ACETYL-L-CYSTEINE IN PATCHES ConcentrationStorage time of N-Acetyl-L-cysteine (%) (weeks) System 5 System 8 0 100100 4 81 97 12 54 90

The above results show that it is possible to improve the stability ofN-Acetyl-L-cysteine in a patch formulation, e.g. by adding a stabilizersuch as sodium bisulfite.

A reservoir type device may be manufactured by heat sealing a membranesuch as described in Example 3 to a backing containing the drug in asuitable vehicle.

An iontophoretic type device may be manufactured essentially accordingto embodiments disclosed in e.g. Parminder Singh et al, “Iontophoresisin Drug Delivery: Basic Principles and Applications”, Critical Reviewsin Therapeutic Drug Carrier Systems, 1994; 11 (2&3):161-213. Theadministration of N-Acetyl-L-cysteine is not disclosed in thisreference. Anyhow it lies within the present invention to modify, usingthe disclosure in the present application, the embodiments according tosaid reference to become suitable for the administration ofN-Acetyl-L-cysteine.

The above examples show that it is possible to administerN-Acetyl-L-cysteine and to control its release rate using all knowntypes of devices for transdermal drug administration.

Transdermal administration of N-Acetyl-L-cysteine can be improved by useof the prodrug concept. N-Acetyl-L-cysteine is by nature hydrophilic andit is known that hydrophilic drugs may permeate the skin to a limitedextent due to an unfavourable partition coefficient between lipids andwater. The hydrophilicity of N-Acetyl-L-cysteine could be reduced bychemical modification of the carboxylic group and/or the thiol group.Several pro-drugs of N-Acetyl-L-cysteine are described in Anne H. Kahnset al., “Prodrugs as drug delivery systems. 107. Synthesis and chemicaland enzymatic hydrolysis kinetics of various mono- and diesterprodrugsof N-Acetyl-cysteine” are disclosed in Internat. J. Pharma,1990;62:193-205, but only with the aim of reducing the metabolism ofN-Acetyl-L-cysteine in the liver or in the intestine; the authors do notdiscuss the utility of such pro-drugs for transdermal administration.Pro-drugs of N-Acetyl-L-cysteine may also possess improvedcharacteristics in patch formulations with respect to degradation ofN-Acetyl-L-cysteine or to decreased possible skin metabolism.

It is evident that the above mentioned Examples may be modified toencompass also metabolites and prodrugs of N-Acetyl-L-cysteine.

The stability of N-Acetyl-L-cysteine can be improved by the addition ofstabilizers, which may prevent degradation of N-Acetyl-L-cysteine. Thestabilizers could be disodium edetate, ascorbic acid, sodium bisulphite,sodium hypophosphite, L-cystin, L-cysteine or other suitable stabilizingcompounds. Adjustment of the protolytic balance, i.e. pH in aqueoussystems, may also increase the stability of patch formulations.

A neglectable degradation of N-Acetyl-L-cysteine, less than 1%, mayproduce compounds with an unpleasant smell. This smell could be maskedby the addition of fragrances or flavouring agents, such as peppermintoil, menthol etc.

As the period of time from the first application of a transdermal deviceaccording to the present invention until a therapeutically effectiveserum level of N-Acetyl-L-cysteine is achieved is in the order 2-3 hoursthe complementary and concomitant use of another administration form maybe of value. Oral, sublingual, buccal, nasal, pulmonary and rectal, orpossibly other transmucosal, administration of N-Acetyl-L-cysteineresults in that the drug reaches the system more rapidly than throughthe transdermal route. As mentioned above said non-transdermaladministration forms have the disadvantage of a lower bioavailabilitythan the transdermal form of administration. Anyhow this disadvantage,and problems related thereto, may be temporarily tolerated if amucolytic effect is desirable in the period of time before thetherapeutic effect is achieved from the transdermal device.

One suitable use of the mentioned forms of administration is toadminister N-Acetyl-L-cysteine through the oral, sublingual, buccal,nasal, pulmonary and rectal, or possibly other transmucosal, route atapproximately the same time as the first transdermal device is applied.Thereafter new transdermal devices are applied to ensure the correctplasma level without further administration through the oral,sublingual, buccal, nasal, pulmonary and rectal, or possibly othertransmucosal, routes. The above concomitant use of differentadministration forms is especially useful in certain situations, suchas, but not exclusively, some time prior to oral presentations,attendance to conferences and visits to theatres, concerts and church.It is thus feasable to market set of formulations including devices fortransdermal administration as well as devices or formulations for oral,sublingual, buccal, nasal, rectal, pulmonary and rectal, and possiblyother transmucosal, administration of N-Acetyl-L-cysteine.

Another envisageable concomitant use according to the present inventionis to apply a second transdermal device while a priorly applied firsttrandermal device is still adhered to the patient's skin while stilldelivering some amount of the drug. The utility behind this use is asfollows. Suppose that the transdermal devices used deliver the drugduring 36 hours. The first evening one such device is applied. Thefollowing evening the device still delivers the drug, though usuallywith a lower flux rate than earlier. If now this second evening a secondtransdermal device is applied while the first one is left on the skinthe fluxes from the first and second device will add to a useful flux asthe flux from the first device successively decreases while the drugfrom the second device only reaches the systemic circulation after somehours. By using transdermal devices in this way a more stabletherapeutically effective plasma level of the drug during an extendedperiod of time is achieved than if for example are used devicesdelivering for 24 hours and being replaced every 24 hours of course alsoother useful combinations of concomitantly used transdermal devices areenvisageable.

As it might be advantageous that the mucolytic effect during certainperiods should be allowed to be minor it might be desirable not to treatmucous and purulent expectorates during too long continuous periods oftime. It is within the present invention to administerN-Acetyl-L-cysteine in such a way that a therapeutically effectivesystemic level of N-Acetyl-L-cysteine prevails mainly during thoseperiods of time during day and night when a mucolytic effect is moredesirable, and, consequently, in such a way that a less thantherapeutically effective systemic level of N-Acetyl-L-cysteine prevailsmainly during those periods of time during day and night when amucolytic effect is less desirable. The above object is achievable byapplying the transdermal device at the appropriate time during day ornight in combination with designing the device with the appropriaterelease profile.

Dosage

Assuming that the oral bioavailability is around 5%, that thetransdermal bioavailability is around 100% and that the usual peroraldose is 200-600 mg/day then the transdermal dose is equivalent to 10-30mg/day. This daily transdermal dose corresponds to a flux rate of 15-45μg/cm²/hour from a transdermal device with an area of 30 cm² under theassumption that no metabolism takes place in the skin and that thedevice delivers the drug during 24 hours.

The area of a transdermal device being convenient for a patient to wearis in the range from 5 to 50 cm². The corresponding patch loading shouldbe at least from about 0.3 mg/cm² to about 1.0 mg/cm² for a transdermaldevice with an area of 30 cm². As the drug content of a transdermaldevice is never completely depleted during its application to a patienta higher loading than above must be anticipated, preferably from about0.5 mg/cm² to about 3.0 mg/cm². The above indicated loadings in mg/cm²are to be considered as average loadings for an average size device. Itis known that the driving force for the release of a drug from atransdermal device is related to the drug concentration, i.e. number ofmg of drug/cm³. Therefore the above indicated loadings in mg/cm² are tobe adjusted according to the actual areal size and thickness of thedevice in order to arrive at the desirable therapeutic effect.

Loadings for different sizes and types of devices for transdermaladministration, taking into account different age groups and types ofpatients, range from about 0.1 mg/cm² to about 10 mg/cm² ofN-Acetyl-L-cysteine. The hourly flux rate of dextromethorphan rangesfrom about 1 μg/cm²/hour to about 100 μg/cm²/hour. The effectivetransdermally delivered amount of N-Acetyl-L-cysteine is from about 0.05mg/kg bodyweight to about 5 mg/kg bodyweight.

It should also be contemplated that a device for transdermal deliveryduring 8-12 hours would be clinically more relevant than a device fordelivery during 24 hours. Such a device with limited release durationmay be used for periods when the problems arising from mucous andpurulent expectorates are most embarassing.

The mentioned device may either be taken off from the skin after 8-12hours in order to stop further delivery, or be designed in such a waythat its delivery drops to negligible or non-pharmacological levelsafter 8-12 hours. In this latter case the device may remain on the skinafter 8-12 hours without the patient risking further delivery thereafterwhich facilitates the patient's handling of the device. Such devices areknown per se, see eg U.S. Pat. No. 4,915,950 (MIRANDA ET AL.)—althoughnot for delivery of N-Acetyl-L-cysteine.

When N-Acetyl-L-cysteine is administered in a transdermal device thelatter should preferably be occlusive, which means that the device doesnot permit water to migrate outwardly from the patient. Thereby thehydration of the skin is increased which favors the penetration ofN-Acetyl-L-cysteine through the skin.

What is claimed is:
 1. A method for achieving a mucolytic effect in aliving body by decreasing the viscosity of mucous and purulentexpectorates, said method comprising transdermally administering acompound comprising N-Acetyl-L-cysteine, optionally encompassing salts,prodrugs and metabolites thereof, and optionally together withpharmaceutically acceptable carrier(s), wherein transdermaladministration is achieved by a transdermal device comprising one ormore layers selected from the group consisting of a membrane or anadhesive polymer.
 2. The method of claim 1, wherein the mucolytic effectis achieved through systemic effect of the transdermally administeredcompound.
 3. The method of claim 1, or 2, wherein the mucolytic effectis achieved through decreasing the viscosity of mucous and purulentexpectorates.
 4. The method of claim 1, wherein the transdermaladministration is carried out using a device for transdermal delivery,such device is selected from the group consisting of reservoir, matrix,drug-in-adhesive, multi-laminate, iontophoretic and combinationsthereof.
 5. The method of claim 1 , wherein more than one device fortransdermal delivery is used at a time.
 6. The method of claim 1,wherein the effective amount of N-Acetyl-L-cysteine is from about 0.05mg/kg bodyweight to about 5 mg/kg bodyweight during a predefined periodof time.
 7. A method for achieving a mucolytic effect in a living bodyby decreasing the viscosity of mucous and purulent expectorates, whichcomprises transdermally administering a compound comprisingN-Acetyl-L-cysteine, optionally encompassing salts, prodrugs andmetabolites thereof, and optionally together with pharmaceuticallyacceptable carrier(s) in combination with oral, sublingual, buccal,nasal, pulmonary, rectal and/or trans-mucosal administration of acompound comprising N-Acetyl-L-cysteine, optionally encompassing salts,prodrugs and metabolites thereof, and optionally together withpharmaceutically acceptable carrier(s).
 8. The method of claim 1,wherein the N-Acetyl-L-cysteine is administered in such a way that atherapeutically effective systemic level of N-Acetyl-L-cysteine prevailsmainly during those periods of time during day and night when amucolytic effect is most desirable.
 9. The method of claim 1, whereinthe N-Acetyl-L-cysteine is administered in such a way that a less thantherapeutically effective systemic level of N-Acetyl-L-cysteine prevailsmainly during those periods of time during day and night when amucolytic effect is less desirable.
 10. The method of claim 6, whereinthe predefined period of time is 8, 12 or 24 hours.